Ferroptosis: CD8+T cells’ blade to destroy tumor cells or poison for self-destruction

Ferroptosis represents an emerging, iron-dependent form of cell death driven by lipid peroxidation. In recent years, it has garnered significant attention in the realm of cancer immunotherapy, particularly in studies involving immune checkpoint inhibitors. This form of cell death not only enhances our comprehension of the tumor microenvironment but is also considered a promising therapeutic strategy to address tumor resistance, investigate immune activation mechanisms, and facilitate the development of cancer vaccines. The combination of immunotherapy with ferroptosis provides innovative targets and fresh perspectives for advancing cancer treatment. Nevertheless, tumor cells appear to possess a wider array of ferroptosis evasion strategies compared to CD8⁺T cells, which have been conclusively shown to be more vulnerable to ferroptosis. Furthermore, ferroptosis in the TME can create a favorable environment for tumor survival and invasion. Under this premise, both inducing tumor cell ferroptosis and inhibiting T cell ferroptosis will impact antitumor immunity to some extent, and even make the final result run counter to our therapeutic purpose. This paper systematically elucidates the dual-edged sword role of ferroptosis in the antitumor process of T cells, briefly outlining the complexity of ferroptosis within the TME. It explores potential side effects associated with ferroptosis-inducing therapies and critically considers the combined application of ferroptosis-based therapies with ICIs. Furthermore, it highlights the current challenges faced by this combined therapeutic approach and points out future directions for development.